Download Fluoxetine Accord capsule, hard ENG SmPC

SUMMARY OF PRODUCT CHARACTERISTICS
1.
NAME OF THE MEDICINAL PRODUCT
Fluoxetine Accord 20 mg capsule, hard
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains 22.4 mg fluoxetine hydrochloride equivalent to 20 mg fluoxetine.
For the full list of excipients, see section 6.1.
3.
PHARMACEUTICAL FORM
Capsule, Hard
Light green opaque / standard yellow opaque, size `3’, hard gelatin capsules with
imprinting “BJ” on cap and “F20” on body containing white to off-white powder.
4.
CLINICAL PARTICULARS
4.1
Therapeutic indications
Adults:
Major depressive episodes.
Obsessive-compulsive disorder.
Bulimia nervosa: Fluoxetine is indicated as a complement of psychotherapy for the
reduction of binge-eating and purging activity.
Paediatric population
Children and adolescents aged 8 years and above:
Moderate to severe major depressive episode, if depression is unresponsive to
psychological therapy after 4-6 sessions. Antidepressant medication should be offered
to a child or young person with moderate to severe depression only in combination
with a concurrent psychological therapy.
4.2
Posology and method of administration
Posology
Adults
Major depressive episodes.
Adults and the elderly: The recommended dose is 20mg daily. Dosage should be
reviewed and adjusted if necessary, within 3 to 4 weeks of initiation of therapy and
thereafter as judged clinically appropriate. Although there may be an increased
potential for undesirable effects at higher doses, in some patients, with insufficient
response to 20mg, the dose may be increased gradually up to a maximum of 60mg
(see section 5.1). Dosage adjustments should be made carefully on an individual
patient basis, to maintain the patients at the lowest effective dose.
Patients with depression should be treated for a sufficient period of at least 6 months
to ensure that they are free from symptoms.
Obsessive-compulsive disorder
Adults and the elderly: The recommended dose is 20mg daily. Although there may be
an increased potential for undesirable effects at higher doses, in some patients, if after
two weeks there is insufficient response to 20mg, the dose may be increased gradually
up to a maximum of 60mg.
If no improvement is observed within 10 weeks, treatment with fluoxetine should be
reconsidered. If a good therapeutic response has been obtained, treatment can be
continued at a dosage adjusted on an individual basis. While there are no systematic
studies to answer the question of how long to continue fluoxetine treatment, OCD is a
chronic condition and it is reasonable to consider continuation beyond 10 weeks in
responding patients. Dosage adjustments should be made carefully on an individual
patient basis, to maintain the patient at the lowest effective dose. The need for
treatment should be reassessed periodically. Some clinicians advocate concomitant
behavioural psychotherapy for patients who have done well on pharmacotherapy.
Long-term efficacy (more than 24 weeks) has not been demonstrated in OCD.
Bulimia nervosa: Adults and the elderly: A dose of 60mg/day is recommended. Longterm efficacy (more than 3 months) has not been demonstrated in bulimia nervosa.
All indications: Adults: The recommended dose may be increased or decreased. Doses
above 80mg/day have not been systematically evaluated.
Paediatric population- Children and adolescents aged 8 years and above (moderate
to severe major depressive episode):
Treatment should be initiated and monitored under specialist supervision. The starting
dose is 10mg/day. Dose adjustments should be made carefully, on an individual basis,
to maintain the patient at the lowest effective dose.
After one to two weeks, the dose may be increased to 20mg/day. Clinical trial
experience with daily doses greater than 20mg is minimal. There is only limited data
on treatment beyond 9 weeks.
Lower-weight children: Due to higher plasma levels in lower-weight children, the
therapeutic effect may be achieved with lower doses (see section 5.2).
For paediatric patients who respond to treatment, the need for continued treatment
after 6 months should be reviewed. If no clinical benefit is achieved within 9 weeks,
treatment should be reconsidered.
Elderly patients: Caution is recommended when increasing the dose, and the daily
dose should generally not exceed 40mg. Maximum recommended dose is 60mg/day.
Hepatic impairment
A lower or less frequent dose (eg, 20mg every second day) should be considered in
patients with hepatic impairment (see section 5.2), or in patients where concomitant
medication has the potential for interaction with fluoxetine (see section 4.5).
Withdrawal symptoms seen on discontinuation of Fluoxetine Capsules: Abrupt
discontinuation should be avoided. When stopping treatment with Fluoxetine Capsules
the dose should be gradually reduced over a period of at least one to two weeks in
order to reduce the risk of withdrawal reactions (see section 4.4 and section 4.8). If
intolerable symptoms occur following a decrease in the dose or upon discontinuation
of treatment, then resuming the previously prescribed dose may be considered.
Subsequently, the physician may continue decreasing the dose, but at a more gradual
rate.
Method of administration
For oral administration.
Fluoxetine may be administered as a single or divided dose, during or between meals.
When dosing is stopped, active drug substances will persist in the body for weeks.
This should be borne in mind when starting or stopping treatment.
The capsule and oral solution forms are bioequivalent.
4.3
Contraindications
Hypersensitivity to fluoxetine or to any of its excipients listed in section 6.1.
Monoamine oxidase inhibitors: Cases of serious and sometimes fatal reactions have
been reported in patients receiving an SSRI in combination with a monoamine oxidase
inhibitor (MAOI), and in patients who have recently discontinued an SSRI and have
been started on a MAOI. Treatment of fluoxetine should only be started 2 weeks after
discontinuation of an irreversible MAOI and the following day after discontinuation of
a reversible MAOI-A.
Some cases presented with features resembling serotonin syndrome (which may
resemble and be diagnosed as neuroleptic malignant syndrome). Cyproheptadine or
dantrolene may benefit patients experiencing such reactions. Symptoms of a drug
interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that
include confusion, irritability and extreme agitation, progressing to delirium and
coma.
Therefore, fluoxetine is contra-indicated in combination with a non-selective MAOI.
Similarly, at least 5 weeks should elapse after discontinuing fluoxetine treatment
before starting a MAOI. If fluoxetine has been prescribed chronically and/or at a high
dose, a longer interval should be considered.
The combination of fluoxetine with a reversible MAOI (eg, moclobemide, linezolid,
methylthioninium chloride (also called methylene blue; a reversible non-selective
MAOI indicated for the treatment of medicinal or chemical product induced
methaemoglobinaemia)) is not recommended. Treatment with fluoxetine can be
initiated the following day after discontinuation of a reversible MAOI.
In exceptional circumstances, linezolid (an antibiotic which is a reversible nonselective MAOI) can be given in combination with fluoxetine provided that there are
facilities for close observation of symptoms of serotonin syndrome and monitoring of
blood pressure.
Fluoxetine is contra-indicated in combination with metoprolol used in cardiac failure
(see section 4.5).
4.4
Special warnings and precautions for use
Paediatric population - children and adolescents under 18 years of age: Suiciderelated behaviours (suicide attempt and suicidal thoughts) and hostility (predominantly
aggression, oppositional behaviour and anger) were more frequently observed in
clinical trials among children and adolescents treated with antidepressants compared
to those treated with placebo. Fluoxetine Capsules should only be used in children and
adolescents aged 8 to 18 years for the treatment of moderate to severe major
depressive episodes and it should not be used in other indications. If, based on clinical
need, a decision to treat is nevertheless taken, the patient should be carefully
monitored for the appearance of suicidal symptoms. In addition, only limited evidence
is available concerning long-term effect on safety in children and adolescents,
including effects on growth, sexual maturation and cognitive, emotional and
behavioural developments (see section 5.3).
In a 19-week clinical trial, decreased height and weight gain was observed in children
and adolescents treated with fluoxetine (see section 4.8). It has not been established
whether there is an effect on achieving normal adult height. The possibility of a delay
in puberty cannot be ruled out (see sections 5.3 and 4.8). Growth and pubertal
development (height, weight, and TANNER staging) should therefore be monitored
during and after treatment with fluoxetine. If either is slowed, referral to a
paediatrician should be considered.
In paediatric trials, mania and hypomania were commonly reported (see section 4.8).
Therefore, regular monitoring for the occurrence of mania/hypomania is
recommended. Fluoxetine should be discontinued in any patient entering a manic
phase.
It is important that the prescriber discusses carefully the risks and benefits of treatment
with the child/young person and/or their parents.
Suicide/suicidal thoughts or clinical worsening
Depression is associated with an increased risk of suicidal thoughts, self-harm and
suicide (suicide-related events). This risk persists until significant remission occurs.
As improvement may not occur during the first few weeks or more of treatment,
patients should be closely monitored until such improvement occurs. It is general
clinical experience that the risk of suicide may increase in the early stages of recovery.
Other psychiatric conditions for which Fluoxetine Capsules is prescribed can also be
associated with an increased risk of suicide-related events. In addition, these
conditions may be co-morbid with major depressive disorder. The same precautions
observed when treating patients with major depressive disorder should therefore be
observed when treating patients with other psychiatric disorders.
Patients with a history of suicide-related events, those exhibiting a significant degree
of suicidal ideation prior to commencement of treatment are known to be at greater
risk of suicidal thoughts or suicide attempts, and should receive careful monitoring
during treatment. A meta-analysis of placebo-controlled clinical trials of
antidepressants drugs in adult patients with psychiatric disorders showed an increased
risk of suicidal behaviour with antidepressants compared to placebo in patients less
than 25 years old.
Close supervision of patients and in particular those at high risk should accompany
drug therapy especially in early treatment and following dose changes. Patients (and
caregivers of patients) should be alerted about the need to monitor for any clinical
worsening, suicidal behaviour or thoughts and unusual changes in behavior and to
seek medical advice immediately if these symptoms present.
Cardiovascular Effects
Cases of QT interval prolongation and ventricular arrhythmia including torsade de
pointes have been reported during the post-marketing period (see sections 4.5, 4.8 and
4.9).
Fluoxetine should be used with caution in patients with conditions such as congenital
long QT syndrome, a family history of QT prolongation or other clinical conditions
that predispose to arrhythmias (e.g., hypokalemia, hypomagnesemia, bradycardia,
acute myocardial infarction or uncompensated heart failure) or increased exposure to
fluoxetine (e.g., hepatic impairment), or concomitant use with medicinal products
known to induce QT prolongation and/or torsade de pointes (see section 4.5).
If patients with stable cardiac disease are treated, an ECG review should be considered
before treatment is started.
If signs of cardiac arrhythmia occur during treatment with fluoxetine, the treatment
should be withdrawn and an ECG should be performed.
Irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid)
Some cases of serious and sometimes fatal reactions have been reported in patients
receiving an SSRI in combination with an irreversible, non-selective monoamine
oxidase inhibitor (MAOI).
These cases presented with features resembling serotonin syndrome (which may be
confounded with (or diagnosed as) neuroleptic malignant syndrome). Cyproheptadine
or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug
interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that
include confusion, irritability and extreme agitation progressing to delirium and coma.
Therefore, fluoxetine is contra-indicated in combination with an irreversible, nonselective MAOI (see section 4.3). Because of the two weeks-lasting effect of the latter,
treatment of fluoxetine should only be started 2 weeks after discontinuation of an
irreversible, non-selective MAOI. Similarly, at least 5 weeks should elapse after
discontinuing fluoxetine treatment before starting an irreversible, non-selective
MAOI.
Serotonin syndrome or neuroleptic malignant syndrome-like events
On rare occasions, development of a serotonin syndrome or neuroleptic malignant
syndrome-like events have been reported in association with treatment of fluoxetine,
particularly when given in combination with other serotonergic (among others, Ltryptophan) and/or neuroleptic drugs. As these syndromes may result in potentially
life-threatening conditions, treatment with fluoxetine should be discontinued if such
events (characterised by clusters of symptoms, such as hyperthermia, rigidity,
myoclonus, autonomic instability with possible rapid fluctuations of vital signs,
mental status changes, including confusion, irritability, extreme agitation, progressing
to delirium and coma) occur and supportive symptomatic treatment should be
initiated.
Mania
Antidepressants should be used with caution in patients with a history of
mania/hypomania. As with all antidepressants, fluoxetine should be discontinued in
any patient entering a manic phase.
Haemorrhage
There have been reports of cutaneous bleeding abnormalities, such as ecchymosis and
purpura with SSRIs. Ecchymosis has been reported as an infrequent event during
treatment with fluoxetine. Other haemorrhagic manifestations (eg, gynaecological
haemorrhages, gastro-intestinal bleedings and other cutaneous or mucous bleedings)
have been reported rarely. Caution is advised in patients taking SSRIs, particularly in
concomitant use with oral anticoagulants, drugs known to affect platelet function (eg,
atypical antipsychotics, such as clozapine, phenothiazines, most TCAs, aspirin,
NSAIDs), or other drugs that may increase risk of bleeding, as well as in patients with
a history of bleeding disorders.
Seizures
Seizures are a potential risk with antidepressant drugs. Therefore, as with other
antidepressants, fluoxetine should be introduced cautiously in patients who have a
history of seizures. Treatment should be discontinued in any patient who develops
seizures or where there is an increase in seizure frequency. Fluoxetine should be
avoided in patients with unstable seizure disorders/epilepsy and patients with
controlled epilepsy should be carefully monitored (see section 4.5).
Electroconvulsive therapy (ECT)
There have been rare reports of prolonged seizures in patients on fluoxetine receiving
ECT treatment; therefore, caution is advisable.
Tamoxifen
Fluoxetine, a potent inhibitor of CYP2D6, may lead to reduced concentrations of
endoxifen, one of the most important active metabolites of tamoxifen. Therefore,
fluoxetine should whenever possible be avoided during tamoxifen treatment (see
section 4.5).
Akathisia/psychomotor restlessness
The use of fluoxetine has been associated with the development of akathisia,
characterised by a subjectively unpleasant or distressing restlessness and need to
move, often accompanied by an inability to sit or stand still. This is most likely to
occur within the first few weeks of treatment. In patients who develop these
symptoms, increasing the dose may be detrimental.
Diabetes
In patients with diabetes, treatment with an SSRI may alter glycaemic control.
Hypoglycaemia has occurred during therapy with fluoxetine and hyperglycaemia has
developed following discontinuation. Insulin and/or oral hypoglycaemic dosage may
need to be adjusted.
Hepatic/Renal function
Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. A
lower dose, eg, alternate day dosing, is recommended in patients with significant
hepatic dysfunction. When given fluoxetine 20mg/day for 2 months, patients with
severe renal failure (GFR <10ml/min) requiring dialysis showed no difference in
plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal
function.
Rash and allergic reactions
Rash, anaphylactoid events and progressive systemic events, sometimes serious
(involving skin, kidney, liver or lung), have been reported. Upon the appearance of
rash or of other allergic phenomena for which an alternative aetiology cannot be
identified, fluoxetine should be discontinued.
Weight loss
Weight loss may occur in patients taking fluoxetine, but it is usually proportional to
baseline body weight.
Withdrawal symptoms seen on discontinuation of SSRI treatment
Withdrawal symptoms when treatment is discontinued are common, particularly if
discontinuation is abrupt (see section 4.8). In clinical trials, adverse events seen on
treatment discontinuation occurred in approximately 60% of patients in both the
fluoxetine and placebo groups. Of these adverse events, 17% in the fluoxetine group
and 12% in the placebo group were severe in nature.
The risk of withdrawal symptoms may be dependent on several factors, including the
duration and dose of therapy and the rate of dose reduction. Dizziness, sensory
disturbances (including paraesthesia), sleep disturbances (including insomnia and
intense dreams), asthenia, agitation or anxiety, nausea and/or vomiting, tremor, and
headache are the most commonly reported reactions. Generally, these symptoms are
mild to moderate; however, in some patients they may be severe in intensity. They
usually occur within the first few days of discontinuing treatment. Generally, these
symptoms are self-limiting and usually resolve within 2 weeks, though in some
individuals they may be prolonged (2-3 months or more). It is therefore advised that
Fluoxetine Capsules should be gradually tapered when discontinuing treatment over a
period of at least one to two weeks, according to the patient's needs (see 'Withdrawal
symptoms seen on discontinuation of Fluoxetine Capsules, section 4.2).
Mydriasis:
Mydriasis has been reported in association with fluoxetine; therefore, caution should
be used when prescribing fluoxetine in patients with raised intraocular pressure or
those at risk of acute narrow-angle glaucoma.
4.5
Interaction with other medicinal products and other forms of interaction
Half-life: The long elimination half-lives of both fluoxetine and norfluoxetine should
be borne in mind (see section 5.2) when considering pharmacodynamic or
pharmacokinetic drug interactions (eg, when switching from fluoxetine to other
antidepressants).
Contra-indicated combinations
Irreversible, non-selective monoamine oxidase inhibitors (e.g. iproniazid): Some cases
of serious and sometimes fatal reactions have been reported in patients receiving an
SSRI in combination with an irreversible, non-selective monoamine oxidase inhibitor
(MAOI).
These cases presented with features resembling serotonin syndrome (which may be
confounded with [or diagnosed as] neuroleptic malignant syndrome). Cyproheptadine
or dantrolene may benefit patients experiencing such reactions. Symptoms of a drug
interaction with a MAOI include: hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, mental status changes that
include confusion, irritability and extreme agitation progressing to delirium and coma.
Therefore, fluoxetine is contra-indicated in combination with an irreversible, nonselective MAOI (see section 4.3). Because of the two weeks-lasting effect of the latter,
treatment of fluoxetine should only be started 2 weeks after discontinuation of an
irreversible, non-selective MAOI. Similarly, at least 5 weeks should elapse after
discontinuing fluoxetine treatment before starting an irreversible, non-selective
MAOI.
Metoprolol used in cardiac failure: risk of metoprolol adverse events, including
excessive bradycardia, may be increased because of an inhibition of its metabolism by
fluoxetine (see section 4.3).
Not recommended combinations
Tamoxifen: Pharmacokinetic interaction between CYP2D6 inhibitors and tamoxifen,
showing a 65-75 % reduction in plasma levels of one of the more active forms of the
tamoxifen, i.e. endoxifen, has been reported in the literature. Reduced efficacy of
tamoxifen has been reported with concomitant usage of some SSRI antidepressants in
some studies. As a reduced effect of tamoxifen cannot be excluded, co-administration
with potent CYP2D6 inhibitors (including fluoxetine) should whenever possible be
avoided (see section 4.4).
Alcohol: In formal testing, fluoxetine did not raise blood alcohol levels or enhance the
effects of alcohol. However, the combination of SSRI treatment and alcohol is not
advisable.
MAOI-A including linezolid and methylthioninium chloride (methylene blue): Risk of
serotonin syndrome including diarrhoea, tachycardia, sweating, tremor, confusion or
coma. If the concomitant use of these active substances with fluoxetine cannot be
avoided, close clinical monitoring should be undertaken and the concomitant agents
should be initiated at the lower recommended doses (see section 4.4).
Mequitazine: risk of mequitazine adverse events (such as QT prolongation) may be
increased because of an inhibition of its metabolism by fluoxetine.
Combinations requiring caution
-
Phenytoin: Changes in blood levels have been observed when combined with
fluoxetine. In some cases manifestations of toxicity have occurred. Consideration
should be given to using conservative titration schedules of the concomitant drug and
to monitoring clinical status.
Serotonergic drugs (lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St.
John’s Wort (Hypericum perforatum)):
There have been reports of mild serotonin syndrome when SSRIs were given with
drugs also having a serotoninergic effect. Therefore, the concomitant use of fluoxetine
with these drugs should be undertaken with caution, with closer and more frequent
clinical monitoring (see section 4.4).
QT interval prolongation: Pharmacokinetic and pharmacodynamic studies between
fluoxetine and other medicinal products that prolong the QT interval have not been
performed. An additive effect of fluoxetine and these medicinal products cannot be
excluded. Therefore, co-administration of fluoxetine with medicinal products that
prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotic (e.g.
phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain
antimicrobial agents (e.g.sparfloxacin, moxifloxacin, erythromycin IV, pentamidine),
anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole,
mizolastine), should be used with caution (see sections 4.4, 4.8 and 4.9).
Drugs affecting haemostasis (oral anticoagulants, whatever their mechanism, platelets
antiaggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical
monitoring, and more frequent monitoring of INR with oral anticoagulants, should be
made. A dose adjustment during the fluoxetine treatment and after its discontinuation
may be suitable (see sections 4.4 and 4.8).
Cyproheptadine: There are individual case reports of reduced antidepressant activity
of fluoxetine when used in combination with Cyproheptadine.
Drugs inducing hyponatremia: Hyponatremia is an undesirable effect of fluoxetine.
Use in combination with other agents associated with hyponatremia (e.g. diuretics,
desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk (see
section 4.8).
Drugs lowering the epileptogenic threshold: Seizures are an undesirable effect of
fluoxetine. Use in combination with other agents which may lower the seizure
threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones,
mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk.
Other drugs metabolised by CYP2D6: Fluoxetine is a strong inhibitor of CYP2D6
enzyme, therefore concomitant therapy with drugs also metabolised by this enzyme
system may lead to drug interactions, notably those having a narrow therapeutic index
(such as flecainide, propafenone and nebivolol) and those that are titrated, but also
with atomoxetine, carbamazepine, tricyclic antidepressants and risperidone. They
should be initiated at or adjusted to the low end of their dose range. This may also
apply if fluoxetine has been taken in the previous 5 weeks.
4.6
Fertility, Pregnancy and lactation
Pregnancy:
Some epidemiological studies suggest an increased risk of cardiovascular defects
associated with the use of fluoxetine during the first trimester. The mechanism is
unknown. Overall the data suggest that the risk of having an infant with a
cardiovascular defect following maternal fluoxetine exposure is in the region of 2/100
compared with an expected rate for such defects of approximately 1/100 in the general
population.
Epidemiological data have suggested that the use of SSRIs in pregnancy, particular in
late pregnancy, may increase the risk of persistent pulmonary hypertension in the
newborn (PPHN). The observed risk was approximately 5 cases per 1000 pregnancies.
In the general population 1 to 2 cases of PPHN per 1000 pregnancies occur.
Fluoxetine should not be used during pregnancy unless the clinical condition of the
woman requires treatment with fluoxetine and justifies the potential risk to the foetus.
Abrupt discontinuation of therapy should be avoided during pregnancy (see section
4.2 “Posology and method of administration”). If fluoxetine is used during
pregnancy, caution should be exercised, especially during late pregnancy or just prior
to the onset of labour, since effects have been reported in neonates: irritability, tremor,
hypotonia, persistent crying, difficulty in sucking or in sleeping. These symptoms may
indicate either serotonergic effects or a withdrawal syndrome. The time to occur and
the duration of these symptoms may be related to the long half-life of fluoxetine (4-6
days) and its active metabolite, norfluoxetine (4-16 days).
Breast-feeding: Fluoxetine and its metabolite, norfluoxetine, are known to be excreted
in
human breast milk. Adverse events have been reported in breast-feeding infants. If
treatment with fluoxetine is considered necessary, discontinuation of breast-feeding
should be considered; however, if breast-feeding is continued, the lowest effective
dose of fluoxetine should be prescribed.
Fertility:
Animal data have shown that fluoxetine may affect sperm quality (see section 5.3).
Human case reports with some SSRIs have shown that an effect on sperm quality is
reversible. Impact on human fertility has not been observed so far.
4.7
Effects on ability to drive and use machines
Fluoxetine has no or negligible influence on the ability to drive and use machines.
Although fluoxetine has been shown not to affect psychomotor performance in healthy
volunteers, any psychoactive drug may impair judgement or skills. Patients should be
advised to avoid driving a car or operating hazardous machinery until they are
reasonably certain that their performance is not affected.
4.8
Undesirable effects
a. Summary of the safety profile
The most commonly reported adverse reactions in patients treated with fluoxetine
were headache, nausea, insomnia, fatigue and diarrhoea. Undesirable effects may
decrease in intensity and frequency with continued treatment and do not generally lead
to cessation of therapy.
b. Tabulated list of adverse reactions
The table below gives the adverse reactions observed with fluoxetine treatment in
adult and paediatric populations. Some of these adverse reactions are in common with
other SSRIs.
The following frequencies have been calculated from clinical trials in adults (n =
9297) and from spontaneous reporting.
Frequency estimate: Very common ( 1/10), common ( 1/100 to <1/10), uncommon
( 1/1,000 to <1/100), rare ( 1/10,000 to <1/1,000).
Very
Common
Common
Uncommon
Rare
Blood and lymphatic system disorders
Thrombocyt
openia,
Neutropenia
Leucopenia
Immune system disorders
Anaphylacti
c reaction
Serum
sickness
Endocrine disorders
Inappropria
te
antidiuretic
hormone
secretion
Metabolism and nutrition disorders
Decreased
appetite1
Hyponatrae
mia
Psychiatric disorders
Insomnia2 Anxiety
Depersonalisa Hypomania
tion
Nervousness
Mania
Elevated
Restlessness mood
Hallucinatio
ns
Euphoric
Tension
mood
Agitation
Libido
Thinking
decreased3
Panic attacks
abnormal
Sleep
Confusion
Orgasm
disorder
abnormal5
Dysphemia
Abnormal
Bruxism
dreams4
Aggression
Suicidal
thoughts and
behaviour 6
Nervous system disorders
Headache Disturbance
in attention
Psychomotor
hyperactivity
Convulsion
Akathisia
Dizziness
Dyskinesia
Dysgeusia
Ataxia
Buccoglossa
-l syndrome
Lethargy
Balance
disorder
Serotonin
syndrome
Somnolence7 Myoclonus
Tremor
Memory
impairment
Eye disorders
Vision
blurred
Mydriasis
Ear and labyrinth disorders
Tinnitus
Cardiac disorders
Palpitations
Electrocardi
ogram QT
prolonged
(QTcF ≥ 450
msec)8
Ventricular
arrhythmia
including
torsade
de
pointes
Vascular disorders
Flushing9
Hypotension
Vasculitis
Vasodilatati
on
Respiratory, thoracic and mediastinal disorders
Yawning
Dyspnoea
Pharyngitis
Epistaxis
Pulmonary
events
(inflammator
y processes
of varying
histopatholo
gy and/or
fibrosis) 10
Diarrhoea Vomiting
Dysphagia
Oesophageal
pain
Nausea
Gastrointestin
al
haemorrhage
Gastrointestinal disorders
Dyspepsia
Dry mouth
11
Hepato-biliary disorders
idiosyncrati
c hepatitis
Skin and subcutaneous tissue disorders
Rash12
Alopecia
Angioedema
Urticaria
Increased
tendency to
bruise
Ecchymosis
Pruritus
Hyperhidrosi Cold sweat
s
Photosensiti
vity reaction
Purpura
Erythema
multiforme
StevensJohnson
syndrome
Toxic
Epidermal
Necrolysis
(Lyell
Syndrome)
Musculoskeletal, connective tissue and bone disorders
Arthralgia
Muscle
twitching
Myalgia
Renal and urinary disorders
Frequent
urination13
Dysuria
Urinary
retention
Micturition
disorder
Reproductive system and breast disorders
Gynaecologi Sexual
cal
dysfunction
14
bleeding
Galactorrhoea
Hyperprolacti
naemia
Erectile
dysfunction
Priapism
Ejaculation
disorder15
General disorders and administration site conditions
Fatigue16
Feeling
jittery
Chills
Malaise
Feeling
abnormal
Mucosal
haemorrhage
Feeling cold
Feeling hot
Investigations
Weight
decreased
Transaminase
s increased
Gammaglutamy
Itransferase
increased
1
Includes anorexia
2
Includes early morning awakening, initial insomnia, middle insomnia
3
Includes loss of libido 4 Includes nightmares
5
Includes anorgasmia
6
Includes completed suicide, depression suicidal, intentional self-injury, self-injurious
ideation, suicidal behaviour, suicidal ideation, suicide attempt, morbid thoughts, self-injurious
behaviour. These symptoms may be due to underlying disease
7
Includes hypersomnia, sedation
8
Based on ECG measurements from clinical trials
9
Includes hot flush
10
Includes atelectasis, interstitial lung disease, pneumonitis
11
Includes most frequently gingival bleeding, haematemesis, haematochezia, rectal
haemorrhage, diarrhoea haemorrhagic, melaena, and gastric ulcerhaemorrhage
12
Includes erythema, exfoliative rash, heat rash, rash, rash erythematous, rash follicular, rash
generalized, rash macular, rash macular-papular, rash morbilliform, rash papular, rash
pruritic, rash vesicular, umbilical erythema rash
13
Includes pollakiuria
14
Includes cervix haemorrhage, uterine dysfunction, uterine bleeding, genital haemorrhage,
menometrorhagia, menorrhagia, metrorrhagia, polymenorrhea, postmenopausal haemorrhage,
uterine haemorrhage, vaginal haemorrhage
15
Includes ejaculation failure, ejaculation dysfunction, premature ejaculation, ejaculation
delayed, retrograde ejaculation
16
Includes asthenia
c. Description of selected adverse reactions
Suicide/suicidal thoughts or clinical worsening: Cases of suicidal ideation and suicidal
behaviour have been reported during fluoxetine therapy or early after treatment
discontinuation (see section 4.4).
Bone fractures: Epidemiological studies, mainly conducted in patients 50 years of age and
older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The
mechanism leading to the risk is unknown.
Withdrawal symptoms seen on discontinuation of fluoxetine treatments: Discontinuation of
fluoxetine commonly leads to withdrawal symptoms. Dizziness, sensory disturbances
(including paraesthesia), sleep disturbances (including insomnia and intense dreams),
asthenia, agitation or anxiety, nausea and/or vomiting, tremor and headache are the most
commonly reported reactions. Generally these events are mild to moderate and are selflimiting, however, in some patients they may be severe and/or prolonged (see section 4.4). It
is therefore advised that when Fluoxetine treatment is no longer required, gradual
discontinuation by dose tapering should be carried out (see sections 4.2 and 4.4).
Paediatric population (see sections 4.4 and 5.1):
Adverse reactions have been observed specifically in this population are described below.
Frequencies for these events are based on paediatric clinical trial exposures (n = 610).
In paediatric clinical trials, suicide-related behaviours (suicide attempt and suicidal thoughts),
and hostility (the events reported were: anger, irritability, aggression, agitation, activation
syndrome), manic reactions, including mania and hypomania (no prior episodes reported in
these patients) and epistaxis, were commonly reported and were more frequently observed
among children and adolescents treated with antidepressants compared to those treated with
placebo.
Isolated cases of growth retardation have been reported from clinical use (See also section
5.1).
In paediatric clinical trials, fluoxetine treatment was associated with a decrease in alkaline
phosphatase levels.
Isolated cases of adverse events potentially indicating delayed sexual maturation or sexual
dysfunction have been reported from paediatric clinical use. (See also section 5.3).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the national
reporting system listed in Appendix V*.
4.9
Overdose
Symptoms
Cases of overdose of fluoxetine alone usually have a mild course. Symptoms of overdose
have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from
asymptomatic arrhythmias (including nodal rhythm and ventricular arrhythmias) or ECG
changes indicative of QTc prolongation to cardiac arrest (including very rare cases of Torsade
de Pointes), to cardiac arrest, pulmonary dysfunction, and signs of altered CNS status ranging
from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been
extremely rare.
Management
Cardiac and vital signs monitoring are recommended, along with general symptomatic and
supportive measures. No specific antidote is known.
Forced diuresis, dialysis, haemoperfusion, and exchange transfusion are unlikely to be of
benefit. Activated charcoal, which may be used with sorbitol, may be as or more effective
than emesis or lavage. In managing overdosage, consider the possibility of multiple drug
involvement. An extended time for close medical observation may be needed in patients who
have taken excessive quantities of a tricyclic antidepressant if they are also taking, or have
recently taken, fluoxetine.
5.
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Selective serotonin reuptake inhibitors.
ATC code: N06A B03.
Mechanism of action
Fluoxetine is a selective inhibitor of serotonin reuptake, and this probably accounts for the mechanism
of action. Fluoxetine has practically no affinity to other receptors such as α1-, α2-, and β-adrenergic;
serotonergic; dopaminergic; histaminergic1; muscarinic; and GABA receptors.
Clinical efficacy and safety
Major depressive episodes: Clinical trials in patients with major depressive episodes have been
conducted versus placebo and active controls. Fluoxetine has been shown to be significantly more
effective than placebo, as measured by the Hamilton Depression Rating Scale (HAM-D). In these
studies, Fluoxetine produced a significantly higher rate of response (defined by a 50% decrease in the
HAM-D score) and remission compared to placebo.
Dose response: In the fixed dose studies of patients with major depression there is a flat dose response
curve, providing no suggestion of advantage in terms of efficacy for using higher than the
recommended doses. However, it is clinical experience that uptitrating might be beneficial for some
patients.
Obsessive-compulsive disorder: In short-term trials (under 24 weeks), fluoxetine was shown to be
significantly more effective than placebo. There was a therapeutic effect at 20mg/day, but higher doses
(40 or 60mg/day) showed a higher response rate. In long-term studies (three short-term studies
extension phase and a relapse prevention study), efficacy has not been shown.
Bulimia nervosa: In short-term trials (under 16 weeks), in out-patients fulfilling DSM-III-R-criteria
for bulimia nervosa, fluoxetine 60mg/day was shown to be significantly more effective than placebo
for the reduction of bingeing and purging activities. However, for long-term efficacy no conclusion
can be drawn.
Two placebo-controlled studies were conducted in patients meeting pre-menstrual dysphoric disorder
(PMDD) diagnostic criteria according to DSM-IV. Patients were included if they had symptoms of
sufficient severity to impair social and occupational function and relationships with others. Patients
using oral contraceptives were excluded. In the first study of continuous 20mg daily dosing for 6
cycles, improvement was observed in the primary efficacy parameter (irritability, anxiety and
dysphoria). In the second study, with intermittent luteal phase dosing (20mg daily for 14 days) for 3
cycles, improvement was observed in the primary efficacy parameter (Daily Record of Severity of
Problems score). However, definitive conclusions on efficacy and duration of treatment cannot be
drawn from these studies.
Paediatric population
Major depressive episodes: Clinical trials in children and adolescents aged 8 years and above have
been conducted versus placebo. Fluoxetine, at a dose of 20mg, has been shown to be significantly
more effective than placebo in two short-term pivotal studies, as measured by the reduction of
Childhood Depression Rating Scale-Revised (CDRS-R) total scores and Clinical Global Impression of
Improvement (CGI-I) scores. In both studies, patients met criteria for moderate to severe MDD (DSMIII or DSM-IV) at three different evaluations by practising child psychiatrists. Efficacy in the
fluoxetine trials may depend on the inclusion of a selective patient population (one that has not
spontaneously recovered within a period of 3-5 weeks and whose depression persisted in the face of
considerable attention). There is only limited data on safety and efficacy beyond 9 weeks. In general,
efficacy of fluoxetine was modest. Response rates (the primary endpoint, defined as a 30% decrease in
the CDRS-R score) demonstrated a statistically significant difference in one of the two pivotal studies
(58% for fluoxetine versus 32% for placebo, P = 0.013; and 65% for fluoxetine versus 54% for
placebo, P = 0.093). In these two studies, the mean absolute changes in CDRS-R from baseline to
endpoint were 20 for fluoxetine versus 11 for placebo, P = 0.002; and 22 for fluoxetine versus 15 for
placebo, P <0.001.
Effects on growth, see sections 4.4 and 4.8:
After 19 weeks of treatment, paediatric subjects treated with fluoxetine in a clinical trial gained an
average of 1.1 cm less in height (p=0.004) and 1.1 kg less in weight (p=0.008) than subjects treated
with placebo.
In a retrospective matched control observational study with a mean of 1.8 years of exposure to
fluoxetine, paediatric subjects treated with fluoxetine had no difference in growth adjusted for
expected growth in height from their matched, untreated controls (0.0 cm, p=0.9673).
5.2
Pharmacokinetic properties
Absorption
Fluoxetine is well absorbed from the gastro-intestinal tract after oral administration. The
bioavailability is not affected by food intake.
Distribution
Fluoxetine is extensively bound to plasma proteins (about 95%) and it is widely distributed
(volume of distribution: 20-40 l/kg). Steady-state plasma concentrations are achieved after
dosing for several weeks. Steady-state concentrations after prolonged dosing are similar to
concentrations seen at 4 to 5 weeks.
Biotransformation
Fluoxetine has a non-linear pharmacokinetic profile with first pass liver effect. Maximum
plasma concentration is generally achieved 6 to 8 hours after administration. Fluoxetine is
extensively metabolised by the polymorphic enzyme CYP2D6. Fluoxetine is primarily
metabolised by the liver to the active metabolite norfluoxetine (desmethylfluoxetine), by
desmethylation.
Elimination
The elimination half-life of fluoxetine is 4 to 6 days and for norfluoxetine 4 to 16 days. These
long half-lives are responsible for persistence of the drug for 5-6 weeks after discontinuation.
Excretion is mainly (about 60%) via the kidney. Fluoxetine is secreted into breast milk.
Special Populations Elderly: Kinetic parameters are not altered in healthy elderly when
compared to younger subjects.
Paediatric population: The mean fluoxetine concentration in children is approximately 2-fold
higher than that observed in adolescents and the mean norfluoxetine concentration 1.5-fold
higher. Steady-state plasma concentrations are dependent on body weight and are higher in
lower weight children (see section 4.2). As in adults, fluoxetine and norfluoxetine
accumulated extensively following multiple oral dosing; steady-state concentrations were
achieved within 3 to 4 weeks of daily dosing.
Hepatic insufficiency: In case of hepatic insufficiency (alcoholic cirrhosis), fluoxetine and
norfluoxetine half-lives are increased to 7 and 12 days, respectively. A lower or less frequent
dose should be considered.
Renal insufficiency: After single-dose administration of fluoxetine in patients with mild,
moderate, or complete (anuria) renal insufficiency, kinetic parameters have not been altered
when compared to healthy volunteers. However, after repeated administration, an increase in
steady-state plateau of plasma concentrations may be observed.
5.3
Preclinical safety data
There is no evidence of carcinogenicity or mutagenicity from in vitro or animal studies.
Adult animal studies
In a 2-generation rat reproduction study, fluoxetine did not produce adverse effects on the
mating or fertility of rats, was not teratogenic, and did not affect growth, development, or
reproductive parameters of the offspring.
The concentrations in the diet provided doses approximately equivalent to 1.5, 3.9, and 9.7
mg fluoxetine/kg body weight.
Male mice treated daily for 3 months with fluoxetine in the diet at a dose approximately
equivalent to 31 mg/kg showed a decrease in testis weight and hypospermatogenesis.
However, this dose level exceeded the maximum-tolerated dose (MTD) as significant signs of
toxicity were seen.
Juvenile animal studies
In a juvenile toxicology study in CD rats, administration of 30mg/kg/day of fluoxetine
hydrochloride on postnatal days 21 to 90 resulted in irreversible testicular degeneration and
necrosis, epididymal epithelial vacuolation, immaturity and inactivity of the female
reproductive tract and decreased fertility. Delays in sexual maturation occurred in males (10
and 30mg/kg/day) and females (30mg/kg/day). The significance of these findings in humans
is unknown. Rats administered 30mg/kg also had decreased femur lengths compared with
controls and skeletal muscle degeneration, necrosis and regeneration. At 10mg/kg/day, plasma
levels achieved in animals were approximately 0.8 to 8.8-fold (fluoxetine) and 3.6 to 23.2fold (norfluoxetine) those usually observed in paediatric patients. At 3mg/kg/day, plasma
levels achieved in animals were approximately 0.04 to 0.5-fold (fluoxetine) and 0.3 to 2.1fold (norfluoxetine) those usually achieved in paediatric patients.
A study in juvenile mice has indicated that inhibition of the serotonin transporter prevents the
accrual of bone formation. This finding would appear to be supported by clinical findings.
The reversibility of this effect has not been established.
Another study in juvenile mice (treated on postnatal days 4 to 21) has demonstrated that
inhibition of the serotonin transporter had long-lasting effects on the behaviour of the mice.
There is no information on whether the effect was reversible. The clinical relevance of this
finding has not been established.
6.
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
The capsule also contains:
starch pregelatinised (maize)
silica colloidal anhydrous
magnesium stearate (E470b)
talc purified.
The capsule shell contains:
quinoline yellow (E104)
erythrosine (E127)
indigo carmine (El32)
titanium dioxide (E171)
gelatin.
The printing ink contains:
shellac glaze(E904)
iron oxide black (El72)
propylene glycol
Ammonium hydroxide
6.2
Incompatibilities
Not Applicable
6.3
Shelf life
3 years
6.4
Special precautions for storage
Do not store above 30°C.
6.5
Nature and contents of container
Fluoxetine Accord are packed in PVC /Aluminum blisters.
Blister packs of 10, 14, 20, 28, 30, 50, 56, 60, 70, 90, 98, and 100 capsules.
Not all pack sizes may be marketed.
6.6
Special precautions for disposal and other handling
Any unused product or waste material should be disposed of in accordance with local
requirements.
7.
MARKETING AUTHORISATION HOLDER
For SE
Accord Healthcare Ltd.
Sage House, 319 Pinner Road
North Harrow, Middlesex
HA1 4HF,
United Kingdom
For other member states:
To be completed nationally
8.
MARKETING AUTHORISATION NUMBER(S)
To be completed nationally.
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
To be completed nationally.
10.
DATE OF REVISION OF THE TEXT
2016-12-02